TNF-like ligand 1A (TL1A) is a member of the tumor necrosis factor (ligand) superfamily, member 15. TL1A is also known as TNFSF15 and VEGI and was identified in 1999 as an angiogenesis inhibitor that suppresses the growth of colon carcinomas in vio (Zhai Y et al., (1999) FASEB J, 13(1): 181-9). The protein is abundantly expressed in endothelial cells and activated cells of the hematopoietic lineage, including monocytes, macrophages, lymphocytes, lamina propria mononuclear cells, dendritic cells and plasma cells but is not expressed in either B or T cells (Tan K B et al. (1997) Gene, 204: 35-46; Prehn J L et al., (2007) J Immunol, 178: 4033-4038). It is also expressed in kidney, lung, prostate and thymus (Tan K B et al., (1997), supra). It is a ligand for TNFRSF25/DR3 and decoy receptor TR6/DcR3 and its expression is inducible by TNF and IL-1α. TNFRSF25/DR3 is a death domain-containing receptor that is upregulated during T cell activation. TL1A induces NF-kappaB activation and apoptosis in TNFRSF25/DR3-expressing cell lines, and in T cells, TL1A can act as a costimulator that increases IL-2 responsiveness and secretion of proinflammatory cytokines both in vitro and in vivo. The interaction of TL1A with DR3 can promote T cell expansion during an immune response (Migone T S et al. (2002) Immunity, 16(3): 479-92). The secreted decoy receptor (DcR3), a soluble protein of the tumor necrosis factor receptor (TNFR) superfamily, blocks the action of TL1A. (Kim S & Zhang L, (2005) J Immunol Methods, 298: 1-8). TL1A has been implicated as a potential therapeutic target in a number of diseases and disorders.
A major cause of lung inflammation in allergy and asthma is Th2 polarization of CD4 T cells with elevated IgE levels and production of IL-13 by NKT cells. TL1A plays a major role in allergic lung inflammation by co-stimulating IL-4 and IL-13 production in NKT cells. Blocking TL1A and DR3 interaction by TL1A antibody or dominant negative TL1A mutant abolishes lung inflammation (Fang L et al., (2008) J Exp Med, 205(5): 1037-48). DcR3, the decoy receptor for TL1A is expressed in several lung and colon carcinomas and in some normal tissues, therefore suggesting a role for TL1A in lung and colon carcinomas. In addition, TL1A has also been reported to be angiostatic and to induce metalloproteinase and IL-8 gene expression (Su W B et al., (2006) Exp Cell Res, 312: 266-277; Kang Y J et al., (2005) Cytokine, 29: 229-235). TL1A and DR3 may also be involved in the pathogenesis of atherosclerosis by increasing the production of proinflammatory cytokines and chemokines and decreasing plaque stability by inducing extracellular matrix-degrading enzymes (Kang Y J et al., (2005), supra). There is also evidence to suggest that TL1A/DR3 is involved in the etiology of rheumatoid arthritis (Bossen C et al., (2006) J Biol Chem, 281(20): 13964-13971).
An association between the expression of TL1A and inflammatory bowel disease has been identified by researchers (Prehn J L et al., (2004) Clin Immunol, 112: 66-77; Bamias G et al., (2003) J Immunol, 171: 4868-4874). Crohn's disease, which is a severe inflammatory bowel disorder, is thought to originate from predisposing genetic and environmental factors that cause an imbalance of effector (proinflammatory) and regulatory T cell responses, resulting in inflammation of the gastrointestinal mucosa and disease. The TL1A/DR3 pathway has been shown to play an important role in intestinal diseases, such as Crohn's disease (Papadakis K A et al., (2005) J. Immunol, 174: 4985-4990; Bamias G et al., (2003), supra) and therefore, blockade of the TL1A/DR3 pathway may offer therapeutic opportunities in this disease.
Death receptors and their ligands play a key role in the maintenance of tissue homeostasis and the physiological regulation of programmed cell death. Binding of a death ligand induces oligomerization of the receptor, recruitment of an adapter protein via a conserved cytoplasmic signalling element termed the death domain, activation of caspases and induction of apoptosis (Young H A et al., (2006) Proc Natl Acad Sci USA, 103(22): 8303-8304). Although death receptors such as Fas/Apo-1/CD95. TNF-R1, TRAIL-R1, TRAIL-R2, or DR3 were initially characterized as inducers of apoptosis, there is growing evidence that these receptors also have non-apoptotic functions, including regulation of the adaptive immune response. Bamias et al., reported that TL1A is expressed by lamina propia dendritic cells and that it functions by increasing the proliferation of memory cells, but not naïve CD4+ T cells, and synergizes with IL-12 and/or low-dose stimulation of the T cell receptor to strongly enhance IFN-γ gene expression (Bamias G et al., (2006) Proc. Natl. Acad. Sci. USA, 103: 8441-8446). IFN-γ expression in the gut has been considered a marker of inflammation and many strategies for treating Crohn's disease rely on broad attempts to suppress the immune-activated state. However, such approaches (steroid treatment and immunosuppressive drugs) do not focus on the gut specifically and therefore have their own complications. Targeted therapies based on the use of antagonists of TNF-α were introduced with success in the 1990s and the results suggest that therapy directed specifically against TL1A or its receptor may provide an alternative targeted therapy for this debilitating disorder.
Current treatments for Crohn's disease include the anti-TNF-α monoclonal antibodies Infliximab (Remicade®; Centocor) and Adalimumab (Humira®; Abbott), as well as anti-inflammatories (e.g., sulfasalazine), cortisone or steroids (e.g., prednisone), immune system suppressors (e.g., 6-mercaptopurine) and antibiotics. However, Infliximab is the only treatment option having a high degree of specificity compared to the other available treatments (Young H A et al., (2006), supra). Although Infliximab is generally well tolerated it can cause a recurrence of tuberculosis infection, worsening of heart failure, demyelinating disease and an increased incidence of lymphoma.
Therefore there remains a need in the art for compositions that can be used in the treatment and diagnosis of diverse inflammatory and immune diseases and disorders.